



United States Patent 2,694,089 O ESS R TIHEE QWERYQEBE T T..'.fO.- -r-" NITROPHENYL-Z-AMINO-1,3-BRORANEDIOL Angelo" .lohn Speziale; Kirk'woqd; and? DavigliB. Gnfli'ii',

Glendale, M212, assignors' to Monsante Chemical Conian St. Louis. Me, a' curpnrafibn of. Delaware N 0 Drawing. Application August 12, 1950, Serial No. 179,084

Claimsls (Cl. 260 -51016) This; inventi'om relates' tcr til-threwlsp nitrophenyl amino -Li-propanediohz more specifically,v this invention acetamido-1-,3-propanediol: thereby forming an: aqueoussolution of acetic acid andthe dl threo-l-p nitrophenybZ amino=-l,3-propanediol.hydrochloride.v The" aqueous solution: ofi the amine hydrochloride' is then maderalkalinei by theadd-ition ofi a strong base thereby precipitatihg' thei'free' amine. The resultant aqueous slurry of dl.-threo-l-p' nitrophenyl-Z-amino-1,3-propanediolis cooled to 20:' C., theamine'filtered therefrom, recovered and dried: Utiliv mg commercial grade materials; this process. consistently resultsin aim-80%" yield of theamine.

It is an object of this invention to provide an=imprdve merit in the process-for the recovery of dlr-threbe-l p-nitroe phenyl-Z-amino-l-,3-propanediol= from an aqueous solution of its water soluble acid salt obtained by the minerah acid hydrolysis. of dli-t-hreo-l-pnitrophenyl 2-acetamido=l3 propanediol in-an-aqueous medium. Further objects will: beco'meapparent from a description of the novel process of this invention. a

Ithas'now been. discovered that if: the aqueous slurry' of dl-threo 1 -p-nitrophenyl-2-amino-l-,S-propanediol; ob tainedby the-neutralizationv of an aqueous solution ofits water soluble. acidsalt" hydrolysis of. dlr-threo-l-p-nitrophenyl-2-acetamidd--1,3 propanediol in an aqueous medium; is cooled to a temperature-below about 5 C., insteadof 203 Q. as=hereto.-= fore used, the yield. of all-three-l-p-nitrophenyl 2-amirro== 1,3-propanediol may be significantly'increaseds According to. a preferred. embodiment of this invent-ion; there-- fore, dl threo-l-p-nitrophenyl 2 acetamido l lipropane-- diol is hydrolyzed with an aqueous solution of a mineral acid, thereby forming an aqueous. solution: oh thetjac'id salt of dl-threo-l-p-nitrophe nyl-2-amino-1,3-propanediol. The aqueous solution of the acid salt of dl threo-l-p-nitrophenyl-2.-amino-1,3-propanediol is thenmade alkalineiby the addition of ammonium hydroxide or an alkali metal hydroxide, thereby precipitating the. free dl-threo-l-p-nitrophenyl-Z-amino-l-,3propanediol. The aqueous slurry of thedl-threo-l-p-nitrophenyli 2-amino-l-,3-propanediol is then cooled to 5 C. or lower and the dl-threo l -p-nitro gherylt-Lamino-l ,3-propanediol filtered therefromiand The following. examples are illustrative of the-novel improved process of this invention:

Exam le I- 50.8 g. of dl-threo-l-p-nitrophenyl-Z-acetamido-1,3- propanediol are heated for one hour at 94-97 C. in a solution containing 250 ml. of water and 58.3 g. of 18 B. hydrochloric acid, thereby forming an aqueous solution of dl-threo-l-p-nitrophenyl-Z-amino-1,3-propanediol hydrochloride. The solution is made alkaline to a pH of 9-9.5 by the addition of 100 ml. of concentrated ammonium hydroxide, thereby precipitating the free dl-threo-l-p-nitrophenyl-Z-amino-1,3-propanediol. The aqueous slurry of dl-threo-1-p-nitrophenyl-2-amino-1,3-

eo= l p-nitrophenylQ-amino-1',3 propanediolr is onepreparedby themineral. acid-r 2,694,089 Patented Nov; 9 1954! 2 propanediol' thus dbtai-n'edi is-co'oledi to 5* and filtered:- The?di-threowlapmitrorihenykZeaminoel;sspropanediol thus: obtained is then: drierh by heating at a; temper atum olf- 60? C; 3613 gi oh substantiallyipure dl-thren--l--pr-nitroi-= phenyl'riaamino' l, 3z-propanediol are: obtained: representing an: 8516952 yield! bhserl out the dl-threot-k-psnitrophenyhz acetamido-i,fl-propanediirltutilizediconsideringit as. pure. The dl-threo-li-pmitrophemylflsaminoat,3+propane diol thus obtainecLis: arw-hite crystalline solid having; a melt-ingipoint' of.- 169L114 1% 6..

Example I! Tthe' procedur'e: Sflt'lfOlZth: in: Example I": is repeated. utiliziingi i'ni place: oh the H30 mlr. of cbncentratedammonium. hydrloxide 33' g. of sodium hydroxide. 'liheequality and. yield: ofdl-threo-lep nitrophenyL Z-amino-d;3 propanediol thusaobftained' are-similarrtoi than obtained Example 'Eheproce'du-re: set forth ini Example I- isirepeated utilizing-viri place 015 the. B00 mi of; concentrated; ammonium hydroxide 43v g.- of= piotassiurni hydra-aide- The quality and yield of dl-thrco-l-p-nitrophenyl-2-aminor1,3-propanediol thus obtained are similar to that. obtained in Example; I: Example lV Thepreeedure set forth in Example? I is repeated. utilize ingdnplac'e of. the" 58i3 g. of 18 Bt hydrochloric acid; 30-'g"; of 66 B'; sulfuric acid, and ut-ilizing place of the- 100" ml. of arnrnoniiinr hydroxide, 37 g. of sodium' hydroxi'dei- The quality and yield of dl threo' l-p-nitrophenyl-Z-artiirio-li3 propanediolthus obtained are similar to that ojht'ai'n'ed iii Examplefll- The unexpected and significant improvement obtained" in the novel improved process of this invention as cornpared to the" process as heretofore used ismade clearly evident by the follhwin'g example:

Example. V

50l8'g; of til-tilted I P-Hit FOpHenYIvZ acetamidlJ-T,3'-pr0*- panediol are heated for one'ho'ur" at 9 1 9 7 C in" a solu-- non-containing250ml,of water and- 58 .3 g. of 1 8 B; hydrochloric acid; thereby forming an aqueous solution of dt' t-hre'o l p=riitrophenyl 2arnino+l 3 =-pr opanedio1 hydrochloride, The selutie s is made: asaline to" a pH of- 9-9z5 By' theaddititiri o'fi roe m1; v j nilltn hydfmfide, thereby precipitating the free dl th'r'eol -nitrdpirenylt'zarninoq'n propanedioli The aqueous slurry of di'-t re 'l -p nitropheHyI-Z amino-l ,3 propane+ diol thus obt'a'i'ried is cooled to20 C; and filtered. The dl-threo -p"-nitr ophenyl'-2-amino i',3 propanediol thus ob taine'd is when dried: by-hc'atin g at atemperature of 60 c 33.7 g*.- ojfi substantial-1y pure dl-thre'o-l -p niiirtipjlienyl-Z arriino liii propanediol are obtained representing a 794% yield based qmthe dl three1-p=nitrophenym-aeetamido I,3-propanediol; utilized considering" it as' 100% pure. The-.dl-thredr-pinitrophenylimanrinw1,3 propanedio1 thus obtained 'is a. crystalline solid; having a melting point oft 139 14 C and identical in quality to the dl-threm II-p-IritrQ henyL-Z-arninh LB -propanediol obtained in Example".-

The. filtrate obtained: from! the: filtration at 20f C; of theaqueous: slurry of dL-threoel ptnitrophenyl=z amino LST-p'rop'anediok as described: above: was then cooled to 5 C1 andseede'da Nor'further precipitate of'th'e'dl-threo- I-p=nitrophenyl:--2-amino lfispropanediol could be made to form; In; view ofith'e: fa'cti no further quantity of the dl-threo-l-p-nitrophehyl-Z-amihmlgilepropanediol' can: be made:- to precipitate when the? filtrates obtained v by filtenin'gith'e aqueousfslurny of thedi-thre'o-l-p-nit1iophenyl+* 2-amino-il',3-.propanediol atiZO (C. is: cooled to 5r Catheincreased yield obtained by initially cooling the aqueous slurry of the dl-threo-l-p-nitrophenyl-Z-amino-1,3-propanediol to 5 C. and filtering is clearly unexpected.

In carrying out the novel improved process of this invention, any of the mineral acids may be utilized in er"- fecting the hydrolysis of the dl-threo-1-p-nitropheny1-2- acetamido-1,3-propanediol. Typical of such acids are hydrochloric acid, sulfuric acid and phosphoric acid. The temperature at which the hydrolysis is carried out may be varied over a wide range, such as in the range of from 3 about 30 C. to about 100 C. Preferably, the temperature is maintained near the boiling point of the reaction mixture.

The aqueous solution of the mineral acid salt of dlthreo l p nitrophenyl 2 amino 1,3 propanediol may be made alkaline by the addition thereto of ammonium hydroxide or any of the alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or lithium hydroxide. It is preferred that a sufiicient quantity of the alkaline agent be added so that the aqueous slurry of the dl-threo-1-p-nitrophenyl-2-arnino-1,3-propanediol have a pH greater than about 8.0, preferably in the range of from about 8.0 to about 14.0.

In order to obtain the increased yield of the dl-threo- 1-p-nitrophenyl-2-amino-1,3-propanediol according to the novel improved process of this invention, the aqueous slurry must be filtered at a temperature below about C. The lower limit of the temperature range at which this aqueous slurry can be filtered and obtain the increased yields of the dl-threo-l-p-nitrophenyl-Z-amino- 1,3-propanediol is governed solely by the crystallizing point of the aqueous slurry. Thus, according to the novel improved process of this invention, the aqueous slurry of dZ-threo-1-p-nitrophenyl-2-amino-1,3-propanediol is filtered at a temperature in the range of below about 5 C. and above the crystallizing point of the aqueous slurry.

What is claimed is:

1. In the process for the recovery of dl-threo-l-pnitrophenyl 2 amino 1,3 propanediol obtained through the hydrolysis of dl-threo-1-p-nitrophenyl-2- acetamido-1,3-propanediol with a mineral acid in an aqueous medium and the subsequent neutralization of the resulting solution of the mineral acid salt with a strong base, the improvement comprising adding said strong base to said aqueous acidic medium until it has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

2. In the process for the recovery of dl-threo-1-pnitrophenyl-Z-amino-l,3-propanediol obtained through the hydrolysis of dl-threo-1-p-nitrophenyl-2-acetamido-1,3-propanediol with a mineral acid in an aqueous medium and the subsequent neutralization of the resulting solution of the mineral acid salt with a strong base, the improvement comprising adding to the acidic aqueous medium immediately following hydrolysis a strong base selected from the group consisting of ammonium hydroxide'and the alkali metal hydroxides until the resulting aqueous medium has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

3 In the process for the recovery of dl-threo-l-pnitrophenyl 2 amino 1,3 propanediol obtained through the hydrolysis of dl-threo-l-p-nitrophenyl-2- acetamido-1,3-propanediol with sulfuric acid in an aqueous medium and the subsequent neutralization of the resulting sulfuric acid salt with a strong base, the improvement comprising adding to the aqueous solution of said sulfuric acid salt immediately following hydrolysis a strong base selected from the group consisting of ammonium hydroxide and the alkali metal hydroxides until the resulting aqueous mixture has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

4. In the process for the recovery of dl-threo-l-pnitrophenyl 2 amino 1,3 propanediol obtained through the hydrolysis of dl-threo-l-p-nitrophenyl-Z- acetamido-l,3-propanediol with hydrochloric acid in an the resulting solution containing the amine hydrochloride with a strong base, the improvement comprising adding to said aqueous solution of amine hydrochloride immediately following hydrolysis a strong base selected from the group consisting of ammonium hydroxide and the alkali metal hydroxides until the resulting aqueous mixture has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallization point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

5. In the process for the recovery of dl-threo-l-pnitrophenyl 2 amino 1,3 propanediol obtained through the hydrolysis of dl-threo-l-p-nitrophenyl-Z- acetamido-1,3-propanediol with hydrochloric acid in an aqueous medium and the subsequent neutralization of the resulting solution containing the amine hydrochloride with a strong base, the improvement comprising adding ammonium hydroxide to said aqueous solution of amine hydrochloride immediately following hydrolysis until the resulting aqueous mixture has a pH greater than 8.0

thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

6. In the process for the recovery of dI-threo-l-p-nitrophenyl-Z-amino-l,3-propanediol obtained through the hydrolysis of dl-threo-1-p-nitrophenyl-2-acetamido-1,3-propanediol with hydrochloric acid in an aqueous medium and the subsequent neutralization of the resulting solution containing the amine hydrochloride with a strong base, the improvement comprising adding sodium hydroxide to said aqueous solution of amine hydrochloride immediately following hydrolysis until the resulting aqueous mixture has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5 C.

7. In the process for the recovery of dl-threo-l-p-nitrophenyl 2 amino 1,3 propanediol obtained through the hydrolysis of d! threo 1 p nitrophenyl 2- acetamido-1,3-propanediol with hydrochloric acid in an ,aqueous medium and the subsequent neutralization of the resulting solution containing the amine hydrochloride with a strong base, the improvement comprising adding potassium hydroxide to said aqueous solution of amine hydrochloride immediately following hydrolysis until the resulting aqueous mixture has a pH greater than 8.0 thereby precipitating the desired free amine, cooling the resulting alkaline slurry to a temperature of from about 5 C. to about the crystallizing point of the slurry and recovering the free amine by filtering said slurry at a temperature below about 5' C.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date Moresch et a1. July 4, 1950 OTHER REFERENCES 

1. IN THE PROCESS FOR THE RECOVERY OF DI-THREO-1-PNITROPHENYL -2 - AMINO - 1,3 - PROPANEDIOL OBTAINED THROUGH THE HYDROLYSIS OF DI-THERO-1-P-NITROPHENYL-2ACETAMIDO-1,3-PROPANEDIOL WITH A MINERAL ACID IN AN AQUEOUS MEDIUM AND THE SUBSEQUENT NEUTRALIZATION OF THE RESULTING SOLUTION OF THE MINERAL ACID SALT WITH A STRONG BASE, THE IMPROVEMENT COMPRISING ADDING SAID STRONG BASE TO SAID AQUEOUS ACIDIC MEDIUM UNTIL IT HAS A PH GREATER THAN 8.0 THEREBY PRECIPITATING THE DESIRED FREE AMINE, COOLING THE RESULTING ALKALINE SLURRY TO A TEMPERATURE OF FROM ABOUT 5* C. TO ABOUT THE CRYSTALLIZING POINT OF THE SLURRY AND RECOVERING THE FREE AMINE BY FILTERING SAID SLURRY AT A TEMPERATURE BELOW ABOUT 5* C. 